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Research ArticleArticle

Selectivity of the Polyspecific Cation Transporter rOCT1 Is Changed by Mutation of Aspartate 475 to Glutamate

Valentin Gorboulev, Christopher Volk, Petra Arndt, Aida Akhoundova and Hermann Koepsell
Molecular Pharmacology December 1999, 56 (6) 1254-1261; DOI: https://doi.org/10.1124/mol.56.6.1254
Valentin Gorboulev
Anatomisches Institut, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
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Christopher Volk
Anatomisches Institut, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
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Petra Arndt
Anatomisches Institut, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
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Aida Akhoundova
Anatomisches Institut, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
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Hermann Koepsell
Anatomisches Institut, Bayerische Julius-Maximilians-Universität, Würzburg, Germany
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Abstract

After site-directed mutagenesis, the organic cation transporter rOCT1 was expressed in Xenopus laevis oocytes or human embryonic kidney cells and functionally characterized. rOCT1 belongs to a new family of polyspecific transporters that includes transporters for organic cations and anions and the Na+-carnitine cotransporter. When glutamate was substituted for Asp475 (middle of the proposed 11th transmembrane α-helix), theV max values for choline, tetraethylammonium (TEA), N 1-methylnicotinamide, and 1-methyl-4-phenylpyridinium were reduced by 89 to 98%. The apparentK m values were also decreased (choline by 15-fold, TEA by 8-fold,N 1-methylnicotinamide by 4-fold) or remained constant (1-methyl-4-phenylpyridinium). After the mutation, the membrane potential dependence of the K mvalue for [3H]choline uptake was abolished. The affinity of n-tetraalkyl ammonium compounds to inhibit TEA uptake was increased. This affinity and its increase by the D475E mutation were increased with the length of the n-alkyl chains. After expression in X. laevis oocytes, the IC50 ratios of wild-type and D475E mutant were 1.7 (tetramethylammonium), 4.3 (TEA), 5.0 (tetrapropylammonium), 5.0 (tetrabutylammonium), and 65 (tetrapentylammonium). Cationic inhibitors with ring structures were differentially affected: the IC50value for TEA inhibition by cyanine 863 remained unchanged, whereas it was increased for quinine. The data suggest that rOCT1 contains a large cation-binding pocket with several interaction domains that may be responsible for high-affinity binding of structurally different cations and that Asp475 is located close to one of these interaction domains.

Footnotes

    • Received May 24, 1999.
    • Accepted August 20, 1999.
  • Send reprint requests to: Prof. Dr. Hermann Koepsell, Anatomisches Institut der Universität, Koellikerstrasse 6, D-97070, Würzburg, Germany, E-mail:anat010{at}mail.uni-wuerzburg.de

  • ↵1 V.G. and C.V. contributed equally to the work.

  • This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 174/A22.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (6)
Molecular Pharmacology
Vol. 56, Issue 6
1 Dec 1999
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Research ArticleArticle

Selectivity of the Polyspecific Cation Transporter rOCT1 Is Changed by Mutation of Aspartate 475 to Glutamate

Valentin Gorboulev, Christopher Volk, Petra Arndt, Aida Akhoundova and Hermann Koepsell
Molecular Pharmacology December 1, 1999, 56 (6) 1254-1261; DOI: https://doi.org/10.1124/mol.56.6.1254

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Research ArticleArticle

Selectivity of the Polyspecific Cation Transporter rOCT1 Is Changed by Mutation of Aspartate 475 to Glutamate

Valentin Gorboulev, Christopher Volk, Petra Arndt, Aida Akhoundova and Hermann Koepsell
Molecular Pharmacology December 1, 1999, 56 (6) 1254-1261; DOI: https://doi.org/10.1124/mol.56.6.1254
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